Acidic mammalian chitinase (AMCase) is a secreted enzyme of molecular weight of about 52.2 kD and typically found in the stomach, salivary gland, and lungs. The enzyme catalyzes the hydrolysis of artificial chitin-like substrates, and is unique among mammalian enzymes by having an acidic pH optimum. AMCase is induced during TH2 inflammation through an IL-13-dependent mechanism. Chitinases are believed to play a key role in the innate immunity to parasites and other infectious agents. It has been suggested that, when produced in a dysregulated fashion, chitinases also play an important role in the pathogenesis of allergy and/or asthma.
Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of reversible airway obstruction and airway hyperresponsiveness (AHR). Typical clinical manifestations include shortness of breath, wheezing, coughing and chest tightness that can become life threatening or fatal. While existing therapies focus on reducing the symptomatic bronchospasm and pulmonary inflammation, there is a growing awareness of the role of long-term airway remodeling in accelerated lung deterioration in asthmatics. Airway remodeling refers to a number of pathological features including epithelial smooth muscle and myofibroblast hyperplasia and/or metaplasia, subepithelial fibrosis and matrix deposition.
It is generally accepted that allergic asthma is initiated by an inappropriate inflammatory reaction to airborne allergens. The lungs of asthmatics demonstrate an intense infiltration of lymphocytes, mast cells and especially eosinophils. AMCase is prominently expressed in lungs from antigen-sensitized and challenged and IL-13-transgenic mice. AMCase mRNA is not readily detected in lung tissues from patients without known lung disease, but has been detected, histologically and morphometrically, in the epithelial cells and subepithelial cells in tissues from patients with asthma. In accordance with TH2 inflammation and IL-13 transgenic models, AMCase is expressed in an exaggerated fashion in lung tissues from patients with asthma.
There is a need in the art for novel compounds that inhibit acidic mammalian chitinase. Such compounds could be used for treating diseases or disorders, such as asthma. The present invention addresses this need.